ABSTRACT Alzheimer's disease (AD) is an incurable and lethal condition with a high prevalence in the US; thus, there is a dire need to find effective treatments for this devastating disorder. Despite considerable effort to investigate the mechanisms of neurotoxicity and characterize the best targets for pharmacological intervention, we still have a very limited understanding of the molecular events underlying AD pathogenesis. For instance, little is know about the molecular targets and mechanisms through which A?42 and tau initiate the pathological cascade and how these two distinct triggers orchestrate the disease. Additionally, recent studies indicate that A?42 and tau display dynamic regulatory interactions and exert synergistic effects. A key challenge, therefore, is to identify critical proteins and pathways capable of blocking concurrent A?42 and tau pathologies. Unfortunately, a target that can robustly override concurrent pathological events is still elusive. To address this, we recently identified a new Drosophila gene that elicits an extraordinary protection against A?42+tau insults in fly models of AD. However, hardly anything is known about this novel gene, which is referred to as RAF2 (RING Associated Factor 2). Therefore, this application aims at defining the therapeutic potential of RAF2 in Drosophila models of AD (Aim 1), and to understand its neuroprotective mechanisms (Aim 2). Our central hypothesis is that RAF2 orchestrates a robust protective program to neutralize A?42 and tau toxicity. Preliminary data in A?42-expressing flies suggests that RAF2 may mediate A?42 degradation, however it is unclear if similar observations would apply in the context of tau or A?42+tau. On the other hand, RAF2 encodes a novel protein of 1,126 amino acids predicted to interact with multiple partners of diverse function. Of note, some of these interactors have human homologues that are associated with AD as either novel candidate genes or risk factors, which highlights the relevance of this work. Moreover, we have generated several RAF2 deletions constructs to define critical regions mediating RAF2 neuroprotection. We anticipate that the experiments proposed here will provide mechanistic insights into the protective role against A?42 and tau toxicity and may lead to the development of new therapeutic strategies for AD.